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Biomedical subjects

D J Gross

Publications and source records attributed to D J Gross.

At least 37 records · Page 2Linked to original sources

Out-of-pocket health spending by poor and near-poor elderly Medicare beneficiaries.

OBJECTIVE: To estimate out-of-pocket health care spending by lower-income Medicare beneficiaries, and to examine spending variations between those who receive Medicaid assistance and those who do not receive such aid. DATA SOURCES AND COLLECTION: 1993 Medicare Current Beneficiary Survey (MCBS) Cost and Use files, supplemented with data from the Bureau of the Census (Current Population Survey); the Congressional Budget Office; the Health Care Financing Administration, Office of the Actuary (National Health Accounts); and the Social Security Administration. STUDY DESIGN: We analyzed out-of-pocket spending through a Medicare Benefits Simulation model, which projects out-of-pocket health care spending from the 1993 MCBS to 1997. Out-of-pocket health care spending is defined to include Medicare deductibles and coinsurance; premiums for private insurance, Medicare Part B, and Medicare HMOs; payments for non-covered goods and services; and balance billing by physicians. It excludes the costs of home care and nursing facility services, as well as indirect tax payments toward health care financing. PRINCIPAL FINDINGS: Almost 60 percent of beneficiaries with incomes below the poverty level did not receive Medicaid assistance in 1997. We estimate that these beneficiaries spent, on average, about half their income out-of-pocket for health care, whether they were enrolled in a Medicare HMO or in the traditional fee-for-service program. The 75 percent of beneficiaries with incomes between 100 and 125 percent of the poverty level who were not enrolled in Medicaid spent an estimated 30 percent of their income out-of-pocket on health care if they were in the traditional program and about 23 percent of their income if they were enrolled in a Medicare HMO. Average out-of-pocket spending among fee-for-service beneficiaries varied depending on whether beneficiaries had Medigap policies, employer-provided supplemental insurance, or no supplemental coverage. Those without supplemental coverage spent more on health care goods and services, but spent less than the other groups on prescription drugs and dental care-services not covered by Medicare. CONCLUSIONS: While Medicaid provides substantial protection for some lower-income Medicare beneficiaries, out-of-pocket health care spending continues to be a substantial burden for most of this population. Medicare reform discussions that focus on shifting more costs to beneficiaries should take into account the dramatic costs of health care already faced by this vulnerable population.

Aged↗

The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice.

The aim of this study was to ascertain the potential usefulness of the antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for "prevention" experiments; and (b) 2-3-mm fragments allowed to grow to 1 cm for "intervention" studies. Both groups received either 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention and intervention experiments, a significant diminution of tumor size and weight was observed in the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor blood flow in linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of tumors from linomide-treated animals revealed marked avascularity. Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels. Taken together, our data indicate that in VHL disease, therapy directed at inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.

Administration, Oral↗

The influence of sequential annual vaccination and of DHEA administration on the efficacy of the immune response to influenza vaccine in the elderly.

The present study examined the effect of repeated vaccination and of dehydroepiandrosterone (DHEA) treatment on the immune response to influenza vaccine in elderly subjects. Seventy-one elderly volunteers, aged 61-89 years, enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for 4 consecutive days starting 2 days before immunization) or placebo. Antibody response against the three strains of vaccine was measured before and 28 days after vaccination, and compared between previously vaccinated and non-vaccinated subjects. DHEA treatment did not enhance established immunity. A significant decrease in attainment of protective antibody titer (titer of 1:40 or greater) against A/Texas in subjects with non-protective baseline antibody titer was recorded following DHEA treatment compared to placebo (52 vs. 84%, P < 0.05). Post-immunization titers against influenza A strains were significantly higher in those subjects who were never immunized before. Additionally, post-vaccination protective titers against the A/Johannesburg strain were more prevalent in those subjects who were never vaccinated before. The results were not the same for anti-B/Harbin antibodies-repeated vaccination caused a non-significant increase in HI titer in previously vaccinated subjects.

Adjuvants, Immunologic↗

Time course of the initial [Ca2+]i response to extracellular ATP in smooth muscle depends on [Ca2+]e and ATP concentration.

In response to extracellular application of 50 microM ATP, all individual porcine aortic smooth muscle cells respond with rapid rises from basal [Ca2+]i to peak [Ca2+]i within 5 s. The time from stimulus to the peak of the [Ca2+]i response increases with decreasing concentration of ATP. At ATP concentrations of 0.5 microM and below, the time to the [Ca2+]i peak varies more significantly from cell to cell than at higher concentrations, and each cell shows complicated initiation and decay kinetics. For any individual cell, the lag phase before a response decreases with increasing concentration of ATP. An increase in lag time with decreasing ATP concentration is also observed in the absence of extracellular Ca2+, but the lag phase is more pronounced, especially at concentrations of ATP below 0.5 microM. Whole-cell patch-clamp electrophysiology shows that in porcine aortic smooth muscle cells, ATP stimulates an inward current carried mainly by Cl- ion efflux with a time course similar to the [Ca2+]i changes and no detectable current from an ATP-gated cation channel. A simple signal cascade initiation kinetics model, starting with nucleotide receptor activation leading to IP3-mediated Ca2+ release from IP3-sensitive internal stores, fits the data and suggests that the kinetics of the Ca2+ response are dominated by upstream signal cascade components.

Adenosine Triphosphate↗

Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immunoregulation combined with Reg protein treatment.

Oral linomide, (quinoline-3-carboxamide), has been shown to prevent autoimmune insulitis, islet destruction, and diabetes in NOD mice treated at an early stage of the disease, but confers only partial protection in animals with advanced disease. Reg protein, the gene product of a complementary DNA isolated from a regenerating rat islet library, has been previously shown to induce expansion of beta-cell mass in pancreatectomized rats. To determine the effect of treatment combining immunomodulation and Reg protein on advanced autoimmune diabetes, we treated female NOD mice with oral linomide and i.p. Reg protein injections. In 14-week-old animals with less severe disease (glucose tolerant), treatment with each agent alone resulted in amelioration of diabetes, as did treatment with Reg alone in 5-week-old prediabetic mice. In 14-week-old animals with more severe disease (glucose intolerant), only treatment with the combination of both agents, but not that with each separately, resulted in amelioration of diabetes. Our study suggests that treatment aimed at abrogation of autoimmunity combined with expansion of beta-cell mass constitutes a potential therapeutic approach for treatment of insulin-dependent diabetes mellitus.

Adjuvants, Immunologic↗

Heterogeneity of epidermal growth factor binding kinetics on individual cells.

Binding of fluorescein-conjugated epidermal growth factor (EGF) to individual A431 cells at 4 degrees C is measured by a quantitative fluorescence imaging technique. After background fluorescence and cell autofluorescence photobleaching corrections, the kinetic data are fit to simple models of one monovalent site and two independent monovalent sites, both of which include a first-order dye photobleaching process. Model simulations and the results from data analysis indicate that the one-monovalent-site model does not describe EGF binding kinetics at the single-cell level, whereas the two-site model is consistent with, but not proved by, the single-cell binding data. In addition, the kinetics of binding of fluorescein-EGF to different cells from the same coverslip often differ significantly from each other, indicating cell-to-cell variations in the binding properties of the EGF receptor.

Binding Sites↗

Fluctuating hyper-hypocortisolaemia: a variant of Cushing's syndrome.

We present a patient with severe Cushing's syndrome secondary to an invasive pituitary tumour. Cortisol secretion fluctuated between severe hypercortisolaemia associated with features of Cushing's syndrome to recurrent symptomatic hypocortisolaemia. Normal ACTH precursors to ACTH ratio during the various stages of cortisol secretion indicated that periodic decreased prohormone processing did not contribute to the unique presentation in the patient. Thus, the the extreme fluctuations of plasma cortisol levels are most probably due to unexplained erratic changes of ACTH secretion.

Adenoma↗

Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes.

OBJECTIVE: von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2) are autosomal dominant cancer syndromes. In both conditions, phaeochromocytoma is a prominent feature. It has recently been suggested that phaeochromocytoma can be the presenting and sole clinical manifestation of these multi-organ syndromes. The aim of this study was to ascertain the incidence of VHL and MEN2 among patients with sporadic phaeochromocytoma by mutational analysis. PATIENTS: Twenty-seven unrelated patients with biochemically and/or anatomically proven sporadic phaeochromocytoma were evaluated. DESIGN AND MEASUREMENTS: Constitutional DNA obtained from the patients was analysed by single stranded conformational analysis (SSCP) for mutations within the VHL gene coding sequence and by denaturing gradient gel electrophoresis (DGGE) for predominant mutations in exons 10, 11 and 16 of the RET proto-oncogene. The incidence of patients positive for either VHL or RET germline mutations was assessed. RESULTS: Twenty-six of 27 patients had normal SSCP patterns in all three VHL gene exon segments and only one patient, with an atypical clinical presentation, had an aberrant pattern in exon 3 which upon DNA sequencing was shown to harbor a G to A transversion mutation at nucleotide 695. All patients had normal RET exon 10, 11 and 16 DGGE migration patterns. CONCLUSION: Most, if not all, patients with typical unilateral sporadic phaeochromocytoma do not have von Hippel-Lindau disease or MEN2. Thus, clinical and/or molecular investigation for von Hippel-Lindau disease and MEN2 in this patient population does not appear to be indicated.

Adolescent↗

Dehydroepiandrosterone treatment is not beneficial to the immune response to influenza in elderly subjects.

BACKGROUND: Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity that was suggested to counter-regulate some phenomena of immunosenescence. Recently, it was shown to reverse the age-associated decline of immune response against influenza vaccine in aged mice. The present study was designed to evaluate the effect of DHEA on the immunization of elderly volunteers against influenza. METHODS: Seventy-one elderly volunteers age 61-89 yr were enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for four consecutive days starting two days before immunization) or placebo. Antibody response to the vaccine was measured before and 28 days after vaccination. RESULTS: DHEA treatment significantly increased serum DHEA-sulfate (DHEA-S). No enhancement in established immunity was observed. A significant decrease in attainment of protective antibody titer (1:40 or higher) against the A/Texas strain in subjects with nonprotective baseline antibody titer was recorded following DHEA treatment compared with placebo (52% vs. 84%, P < 0.05). Baseline DHEA-S serum levels were inversely related to attainment of immunization in DHEA-treated subjects. Influenza-like morbidity during the winter was low in the study group with no difference between the DHEA and placebo groups. CONCLUSIONS: Although highly effective in aged rodents, a short course of DHEA treatment did not improve the age-related declined response to immunization against influenza in human subjects. Higher baseline DHEA-S levels are not predictive of better immunization against influenza in the elderly.

Aged↗

Characterization of the unusual insulin of Psammomys obesus, a rodent with nutrition-induced NIDDM-like syndrome.

Psammomys obesus fed a high-calorie diet develops a NIDDM-like syndrome. The use of reverse-phase high-performance liquid chromatography (HPLC) to study Psammomys insulin biosynthesis and release revealed a very delayed elution time for the Psammomys insulin peak appearing near the position of human proinsulin. This unusual peak was initially thought to represent partially processed insulin on the basis of its molecular size and susceptibility to trimming by carboxypeptidase B (CpB). However, the findings of an active carboxypeptidase E (CpE) enzyme and the normal amidated forms of gastrin and cholecystokinin octapeptide (CCK-8) in Psammomys tissues were inconsistent with CpE-related aberrant processing of insulin. Moreover, amino acid sequencing of the delayed peak of Psammomys insulin revealed fully processed insulin with amino acid sequence as predicted by the cDNA. The unique presence of a B-30 phenylalanine residue, resulting in an increased hydrophobicity of the insulin molecule, probably underlies the marked delay in elution time on HPLC. The unusual structure of Psammomys insulin does not appear to contribute to the proinsulinemia observed in diabetic Psammomys since the HPLC-purified molecule did not inhibit PC1 and PC2 convertase activities in an in vitro assay.

Amino Acid Sequence↗

From sand rats to diabetic patients: is non-insulin-dependent diabetes mellitus a disease of the beta cell?

It has been debated for the past two decades whether non-insulin-dependent diabetes mellitus (NIDDM) is caused by insulin deficiency or insulin resistance. In this review we summarise the data which unequivocally indicate that insulin response to glucose is grossly deficient in patients with impaired glucose tolerance and NIDDM. Furthermore, we review the findings for Psammomys obesus (the sand rat), an animal with spontaneous obesity, insulin resistance and diabetes which has been used as the prototype for "hyperinsulinaemic NIDDM". A large proportion of circulating insulin in this animal consists of proinsulin and its split products, apparently resulting from hyperglycaemia-driven overstimulation of the beta cell, with depletion of its insulin stores. In vitro studies demonstrate that this "glucose toxic" effect can be reproduced in Psammomys islets but not in those of normal rats. This would indicate that increased demand for insulin production leads to aberrations in proinsulin production and processing only in beta cells with inherent (genetic?) defects. We also point to clinical findings which cast doubt on the practical importance of insulin resistance for the glucose homeostasis of NIDDM patients. In these cases, moderate doses of insulin administered by insulin pumps can induce near-normoglycaemia in NIDDM.

Animals↗

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.

Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.

Adrenal Gland Neoplasms↗

Pre-clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients.

OBJECTIVE: Autonomous cortisol secretion without clinical stigmata of Cushing's syndrome (CS) has been recently recognized and termed pre-clinical or sub-clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre-clinical CS among obese patients with uncontrolled diabetes. PATIENTS AND DESIGN: (1) In a retrospective analysis, the medical records of 63 patients with endogenous CS were reviewed. (2) In a cross-sectional study, 90 obese patients (BMI > 25 kg/m2) followed in a University Hospital and the local Health Fund endocrine and diabetes clinics, with poorly controlled diabetes (glycosylated haemoglobin > 9%), underwent an overnight 1 mg dexamethasone suppression. In patients with non-suppressible cortisol levels (> 140 nmol/l), Liddle's 2 and 8 mg dexamethasone suppression tests and imaging studies were performed. MEASUREMENTS: The prevalence of poorly controlled diabetes, the major presenting symptom of CS, was assessed in the retrospective analysis. The prevalence of "true' CS and the false positive rate in the overnight dexamethasone suppression test were calculated. The endocrine evaluation of the patients with pre-clinical CS and the effects of surgical cure on glycaemic control are described. RESULTS: In the retrospective analysis, 11 (17.5%) had diabetes and 2 (3.2%) lacked the classic physical characteristics of the syndrome. In the cross-sectional study, 4 patients failed to suppress plasma cortisol (< 140 nmol/l). In one patient the diagnosis of CS was not confirmed by a standard Liddle's test and was therefore considered false positive. In the other 3, the diagnosis of CS was confirmed (prevalence of 3.3%, 95% confidence interval 1-9%). In all other patients the overnight cortisol suppression test was normal (cortisol level 47.3 +/- 2.5 nmol/l (mean +/- SEM)). After surgical treatment of CS, glycaemic control was markedly improved in all 5 patients (2 from retrospective and 3 from cross-sectional studies). CONCLUSIONS: The prevalence of pre-clinical Cushing's syndrome in obese patients with poorly controlled diabetes appears to be considerably higher than previously believed. The overnight dexamethasone suppression test proved to be a simple, sensitive and highly specific screening test for Cushing's syndrome despite the presence of obesity and hyperglycaemia.

Adult↗